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INTRODUCTIONGenetic contributions to Alzheimer’s Disease (AD) are likely polygenic and not necessarily explained by uniformly applied linear and additive effects. In order to better understand the genetics of AD, we require statistical techniques to address both polygenic and possible non-additive effects.METHODSWe used partial least squares-correspondence analysis (PLS-CA)—a method designed to detect multivariate genotypic effects. We used ADNI-1 (N = 756) as a discovery sample with two forms of PLS-CA: diagnosis-based and ApoE-based. We used ADNI-2 (N= 791) as a validation sample with a diagnosis-based PLS-CA.RESULTSWith PLS-CA we identified some expected genotypic effects (e.g., APOE/TOMM40, and APP) and a number of new effects that include, for examples, risk-associated genotypes in RBFOX1 and GPC6 and control-associated genotypes in PTPN14 and CPNE5.DISCUSSIONThrough the use of PLS-CA, we were able to detect complex (multivariate, genotypic) genetic contributions to AD, which included many non-additive and non-linear risk and possibly protective effects.

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